People suffering from visual impairment face many challenges in performing routine daily activities and/or may not be able to fully enjoy the visual aspects of their surroundings. Of particular concern are visual impairments caused by damage to the retina, which occur in conditions such as age-related macular degeneration (AMD), diabetic retinopathy, and retinopathy of prematurity.
Age-related macular degeneration (AMD) is the leading cause of blindness among adults over the age of 60 in the Western world [Klein, Peto et al., (2004)] with approximately 2 million people suffering from AMD in the US and over 7 million more people at risk (Friedman, O'Colmain et al., 2004). AMD is a multifactorial disease that affects the central (or macular) portion of the retina, the light-sensitive tissue that lines the back of the eye and is responsible for central vision and the detection of fine detail (or acuity).
The acute loss of central vision associated with the wet, or neovascular, form of AMD is the result of unstable, new abnormal blood vessels that grow into the back of the eye where they interfere with normal vision. Prevention of this pathological process, termed choroidal neovascularization, or CNV, is the major target for treatment of the “wet” form of AMD. In AMD patients, CNV is strongly associated with hypoxia and chronic inflammation. These events typically precede CNV, and are thought to play an underlying role in the induction of the neovascular process.
There is a critical need for alternative and more effective treatments for AMD because, for example, the existing treatment requires multiple, costly injections into the eye with the possibility of infection.
Diabetic retinopathy is a progressive disease characterized by abnormalities of the blood vessels of the retina, such as weakening of the blood vessel walls, leakage from the blood vessels, and bleeding and scarring around new vessels. Diabetic retinopathy results in impairment of a person's vision causing severely blurred vision and, potentially, blindness. The World Health Organization indicates that diabetes afflicts 120 million people worldwide, and estimates that this number will increase to 300 million by the year 2025. Diabetic retinopathy is a form of visual impairment often suffered by diabetics.
Due to significant medical advancements, diabetics are able to live much longer than in the past. However, the longer a person has diabetes the greater the chances of developing diabetic retinopathy. Affecting over 5.3 million Americans, diabetic retinopathy is the leading cause of blindness among adults in the United States. Annually, in the United States, between 12,000 and 24,000 people lose their sight because of diabetes.
While management of diabetic retinopathy has improved, risk of complications, such as loss of visual acuity, loss of night vision and loss of peripheral vision, remains significant. Currently, laser photocoagulation is the most effective form of therapy for advanced disease. Unfortunately, current treatment options are inadequate and the disease is often progressive even with successful glucose control.
Retinopathy of prematurity (ROP) is a disorder of retinal blood vessel development in the premature infant. Under normal development, blood vessels grow from the back central part of the eye out toward the edges. In premature babies, this process is not complete and the abnormal growth of the vessels proliferates leading to scar tissue development, retinal detachment and possibly complete blindness.
ROP is the major cause of blindness in children under the age of seven. Improved care in the neonatal intensive care unit has reduced the incidence of retinopathy of prematurity in moderately premature infants. Ironically, however, increasing rates of survival of very premature infants, who would have had little chance of survival in the past, have increased the occurrence of ROP.
Current research shows promise that the prevention of retinal blood vessel damage, which marks retinopathy, may be achieved by the utilization of certain compounds. For example, it has been demonstrated that, in retinal epithelial cells, glutamine deprivation can lead to upregulation of vascular endothelial growth factor (VEGF) expression (Abcouwer S. et al., “Response of VEGF expression to amino acid deprivation and inducers of endoplasmic reticulum stress,” Invest Ophthalmol Vis Sci, August 2002, pp. 2791-8, Vol. 43, No. 8). Most sick premature infants are deprived of glutamine during the time they receive supplemental oxygen, a known predisposing factor in the development of ROP. The over expression of VEGF during this time period is also thought to be involved in the pathogenesis of ROP.
Endostatin, a 20 kDa proteolytic fragment of the carboxy terminus of collagen XVIII, was discovered in 1997. It was the first endogenous inhibitor of angiogenesis identified as a fragment of a matrix protein. By binding multiple receptors and initiating numerous intracellular pathways, endostatin elicits a broad spectrum of anti-proliferative, anti-migratory, and apoptotic effects on the endothelial cells that line the walls of blood vessels.
Although the delivery of anti-angiogenic agents has been shown to result in the destruction of newly formed blood vessels the constant presence of an anti-angiogenic agent, such as endostatin, may result in long-term deleterious effects on normal vessels in the eye.